Matrix metalloproteinases (MMPs) are a family of structurally related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic development, reproduction and tissue remodeling as well as pathological conditions such as rheumatoid arthritis (RA), osteoarthritis (OA), osteoporosis, atherosclerosis and tumor metastasis. MMP family comprises of more than 20 members in human including collagenases (MMP-1, MMP-8, MMP-13), gelatinases (MMP-2, MMP-9), stromelysins (MMP-3, MMP-10, MMP-11), matrilysins (MMP-7, MMP-26), membrane-type (MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, MMP-25), as well as metalloelastases (MMP-12, MMP-19, MMP-20, MMP-22, MMP-23) (Nat Rev Drug Discov., 2007, 6, 480-98).
The most significant members of the MMP family with respect to OA pathology are the collagenases (MMP-1, -8, and -13) which are responsible for type II collagen breakdown (Nat Rev Drug Discov 2007, 6, 480-98; Semin Cell Dev Biol, 2008, 19, 61-8). In recent years, increasing evidence suggests that MMP-13 is the main collagenase responsible for degradation of type II collagen in OA. MMP-13 is not found in normal adult tissues but is specifically expressed in the articular cartilage of OA patients (J Rheumato., 11996, 23, 590-5; J Clin Invest 1996, 97, 2011-9; J Clin Inves., t1996, 97, 761-8; J Clin Invest., 1997, 99, 1534-45). Analysis of human OA cartilage shows a correlation between presence of MMP-13 and MMP-specific collagen cleavage products with disease severity (Arthritis Rheum., 1983, 26, 63-8; J Rheumatol., 2005, 32, 876-86). In vitro data demonstrate that MMP-13 selective inhibitors prevent cytokine-induced collagen loss in human and bovine cartilage ex-plant cultures (Arthritis Rheum. 2009, 60, 2008-18; J Biol Chem 2007 282, 27781-91).
Preclinical models of OA have elevated MMP-13 expression and MMP-13-induced collagen cleavage products in cartilage, synovial fluid, and urine which have been shown to correlate with disease progression (Osteoarthritis Cartilage 2005 13, 139-45; Arthritis Rheum., 1998 41, 877-90). Transgenic mice expressing active human MMP-13 through a cartilage-specific promoter demonstrate pathological changes in articular cartilage of the mouse joints similar to those observed in human OA (J Clin Invest., 2001 107, 35-44; Arthritis Rheum., 2003 48, 1077). In contrast, MMP-13 deficient mice show significantly reduced cartilage degradation as compared to the wild-type following destabilization of the medial meniscus (Arthritis Rheum., 2009 60, 3723-33). Lastly, an orally active MMP-13 selective inhibitor was chondroprotective in rat medial meniscus tear (MMT), rabbit and dog anterior cruciate ligament/medial menisectomy models of OA (Arthritis Rheum., 2009 60, 2008-18; J Biol. Chem., 2007 282, 27781-91, Arthritis Rheum., 2010 62, 3006-15). Taken together, these data indicate that MMP-13 plays an important role in development and progression of the OA in preclinical models and that selective inhibition of MMP-13 can halt breakdown of cartilage thereby preventing joint destruction.
The catalytic zinc domain in MMPs has been the primary focus of inhibitor design. The modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides (Drug Discov Today, 2007 12, 640-6). Over the last 10-15 years, many non-selective MMP inhibitors have advanced to Phase II clinical trials in treatment of diseases such as cancer, rheumatoid arthritis and OA. However, none of these inhibitors have advanced to late stage trials due to a number of significant challenges: A) Highly variable pharmacokinetics and often poor oral bioavailability. B) All of these non-selective inhibitors target the zinc-binding site which is common to all matrix metalloproteinases. The clinical utility of non-selective MMP inhibitors has been restricted by dose-dependent musculoskeletal effects in humans [joint stiffness, inflammation, pain in arms and shoulders termed “musculoskeletal syndrome” (MSS)] (Arthritis Res Ther., 2007 9, R109). No specific MMP has been implicated in MSS and it is believed that non-selective inhibition of multiple MMPs is the primary cause of this toxicity. Although no specific MMP has been implicated in MSS, there is substantial evidence that MMP-13 does not play a major role in development of MSS. Clinical data from humans with mis-sense mutation of MMP13 are characterized by defective growth and modeling of vertebrae and long bones and do not exhibit signs of MSS (J Clin Invest., 2005 115, 2832-42). Preclinical data from mice deficient of MMP-13 also demonstrate growth defects but no histological signs of fibrodysplasia (MSS) (Development, 2004 131, 5883-95). Finally, a 2-week rat model of fibrodysplasia (MSS) study has shown that animals dosed with a highly selective MMP-13 inhibitor do not develop histological signs of fibrodysplasia as compared to animals dosed with a pan-MMP inhibitor (Arthritis Rheum., 2009 60, 2008-18); (J Biol Chem 2007 282, 27781-91).
Hence, there continues to be a need to find new selective MMP-13 inhibitors with an acceptable therapeutic window making them clinically attractive in the treatment of diseases.